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Published ahead of print on February 14, 2003, doi:10.1165/rcmb.2003-0007OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 29, pp. 225-231, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2003-0007OC

Human Leukocyte Antigen-DR Alleles Influence the Clinical Course of Pulmonary Sarcoidosis in Asian Indians

Surendra K. Sharma, Arumugam Balamurugan, Ravindra M. Pandey, Pradip Kumar Saha and Narinder K. Mehra

Departments of Medicine, Transplant Immunology and Immunogenetics, and Biostatistics, All India Institute of Medical Sciences, New Delhi, India

Address correspondence to: Dr. Surendra K. Sharma, Professor, Department of Medicine, All India Institute of Medical Sciences, New Delhi 110 029, India. E-mail: surensk{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Host genetic factors are known to contribute to disease susceptibility and course in sarcoidosis. They may also be important in defining the pattern of disease presentation and progression, as well as its overall prognosis. We have studied human leukocyte antigen (HLA) class I (n = 31) and class II alleles (n = 56) in a cohort of Indian patients with sarcoidosis and 275 healthy control subjects from north India. Although no specific HLA class I allele association was found among sarcoidosis, the functional classification of HLA-A, -B, and -Cw alleles into supertypes revealed an increased frequency of group 2 ligands (Cw2, Cw4, Cw5) for the Killer cell Ig-like receptors (KIR2DL1) in the patient group as compared with control subjects. Among class II alleles, positive association of DRB1*11, DRB1*14, DQA1*0101/4, and DQB1*0503 alleles with the disease was noticed. Clinical follow-up of the patient cohort up to a 5-yr period showed a predominant occurrence of DRB1*14 and its linked DQ alleles in patients with insidious onset, advanced disease on chest radiographs, and chronic course with frequent relapses on tapering off the prednisolone treatment. Further, multivariate logistic regression analysis revealed that the presence of DRB1*11(odds ratio [OR] 9) and DRB1*14 (OR 7), and absence of DRB1*07 (OR 63 and DQB1*0201(OR 3) alleles, were independent predictors of sarcoidosis. The present findings imply that HLA-associated genetic factors influence the risk for the development of sarcoidosis and disease progression.

Abbreviations: human leukocyte antigen, HLA • killer cell immunoglobulin-like receptors, KIR • polymerase chain reaction, PCR • natural killer cell, NK cell • sequence-specific oligonucleotide probe, SSOP


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Sarcoidosis, a multisystemic granulomatous disorder of unknown etiology, occurs in almost all populations, with prevalence differing in each population on the basis of geographical location and racial differences. It affects predominantly the young and middle-aged adults in both sexes (1). Clinical manifestations are characterized by the presence of noncaseating granulomas and numerous immunologic abnormalities. It has been recognized that granulomas are formed as a result of exaggerated cellular immune response to one or more external or self-antigens and subsequent accumulation of hyperactive macrophages and CD4+ T cells at the inflammatory site. Although no evidence for the presence of pathogenic organism(s) has been found at the center of granulomas, the immunologic pattern of cells at the site suggests the role of an exogenous antigen for the cause of disease (2, 3). Also the characteristic features of the cells in sarcoid granulomas share a common immunologic pathway, as noticed in other granulomatous disorders such as mycobacterial and fungal infections. Thus the diagnosis of sarcoidosis is always obscure among Indian patients particularly because of the prevailing high incidence of mycobacterial disease (both tuberculosis and leprosy) in the subcontinent (4). However, studies in the recent years have reported on the extent of disease severity and the prevalence of sarcoidosis in India (5–7).

Environmental exposure to undefined sarcoidosis antigen(s) that cause disease development, differences in the prevalence and clinical manifestations in various ethnic groups, as well as occurrence of familial clusters, point toward an important role of genetic factors in determining disease presentation and overall prognosis (3, 8). At the site of infection, the accumulation of activated T cells are the result of interaction between the T cell receptors and specific human leukocyte antigens (HLA) expressed on the surface of antigen-presenting cells (9). Further, the findings of certain T cell receptors expressed by pulmonary T cells and association of HLA alleles indicates the presence of specific disease causing antigen(s) among susceptible hosts (10, 11). Numerous studies have reported an association of HLA antigens with sarcoidosis with variable alleles in different ethnic groups (12–19). This could possibly be due to the mixed ethnic origin or clinical categories of the study subjects and also methodologies employed for the typing of HLA alleles. Additionally, the recent genomic updates and diversity studies in the HLA system have revealed an ethnically dependent distribution of HLA alleles in various populations (20–23). Although the reported studies on sarcoidosis have indicated heterogeneity in HLA allelic association in different populations, no such genetic study is available in Indian patients. Therefore, to identify the significance of HLA alleles in the development of sarcoidosis in the North Indian population, we investigated the HLA class I and class II alleles in patients and healthy control subjects from the same ethnic background and belonging to the states of Punjab, Haryana, Uttar Pradesh, and Delhi.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Fifty-six patients with sarcoidosis, with an average mean age of 43 ± 8.83 yr, who presented to the Outpatient Department of Internal Medicine or admitted in the tertiary care center, All India Institute of Medical Sciences hospital, New Delhi, between 1996–2000 were included in the study. All patients were diagnosed based on the presence of clinical symptoms, radiographic features compatible with sarcoidosis, and biopsy evidence of noncaseating epithelioid cell granuloma. The clinical characteristics and results of the laboratory investigations including complete hemogram, serum biochemistry, and Mantoux test (5 TU) were carefully recorded during the initial presentation as well as subsequent follow up. The clinical stage of the disease was classified based on the chest radiographic findings at the initial presentation. The patient cohort thus consisted of 24 stage I cases that had bilateral hilar lymphadenophathy without parenchymal infiltrates, 29 stage II cases with bilateral hilar lymphoadenophathy along with parenchymal infiltrates, and 3 stage III cases that had parenchymal infiltrates without hilar lymphadenophathy. Further, 24-h urinary calcium excretion on a restricted milk calcium diet (n = 34) and radiographs of joints (n = 29) were also performed in a proportion of the patients. Definitive histopathologic evidence for disease was frequently obtained from biopsies of liver (n = 5), lymph nodes (n = 22), skin (n = 21), and lungs (n = 20). Biopsies were performed albeit rarely in other sites such as lip, bone (n = 2), parotid gland, and muscle. Multiple biopsies were positive in 16 patients. Patients with evidence of mycobacterial, fungal, and/or parasitic infections, and those with a history of exposure to organic/inorganic material known to cause granulomatous lung disease, were excluded from the study. The institutional ethics committee approved the study proposal, and informed written consent was obtained from each study subject.

Pulmonary Functions
The lung volumes and their subdivisions were measured using a constant volume variable body pressure body plethysmograph (P.K. Morgan, Chatham, Kent, UK) as described previously (24). Pulmonary diffusing capacity (DLCO) was measured by the steady state technique using Rahn and Otis end-tidal sampler for obtaining alveolar air (25).

HLA Typing
Lymphocytes were isolated from the heparinized blood, and subsequently the enriched T cell population was obtained using nylon wool separation columns. The HLA class I (HLA-A, -B, and -Cw) phenotypes were determined in all patients and healthy control subjects using the standard two-stage NIH microlymphocytotoxicity assay. For HLA class II typing, the genomic DNA was extracted from peripheral blood mononuclear cell pellets by using standard salting-out method. Locus-specific primers (both 3' and 5') were used to amplify the exon-two regions of HLA-DR and DQ loci as recommended by the 12th International Histocompatibility Workshop Committee (IHWC, Paris, France). Further, DRB1 allele-specific PCR amplification for high resolution typing of DR2, DR5, and DR6 was performed using generic DRB1 3' primer along with the specific 5' primers for DR2B1 (TTCCTgTggCAgCCTAAgAgg) and DR52B1 (CACgTTTCTTggAgTACTCTAC) alleles. The locus/allele specific amplified DNA was then dot blotted on the nylon membranes (Hybond-N+; Amersham International, UK) to typify the HLA class II allele profile by using sequence-specific oligonucleotide probe hybridization technique. The detailed procedure for PCR cycling parameters and hybridization conditions has already been published elsewhere (26).

Immunogenetic Analysis
The individual phenotypic frequencies of HLA class I (A, B, and Cw) antigens and class II alleles were compared between patients and healthy control subjects. The healthy control subjects (n = 275) belonged to the same socioeconomic and ethnic background as the patients. These were carefully screened for any history of granulomatous or other related disorders. Data on high-resolution typing of HLA-DRB1 alleles was compared with that of 123 healthy unrelated control subjects from the total healthy subjects. Because the high degree of polymorphism has become a major obstacle for demonstrating the single antigen/allelic association in class I, we classified the HLA-A and -B locus specificities into nine functionally different supertypes as suggested by Sette and Sidney (27). Similarly, the HLA-Cw antigens, which are major ligands for the killer cell Ig-like receptors (KIR), were grouped into two different allotypes, namely KIR2DL1 (Cw2, Cw4, Cw5) and KIR2DL2 (Cw1, Cw3, Cw7).

Statistical Analysis
Data were recorded on a predesigned proforma and managed on an excel spreadsheet. All entries were checked for any possible error. Descriptive statistics for categorical variables was performed by computing the frequencies (%) in each category. The association between two categorical variables was evaluated by the {chi}2 tests. To determine various HLA class I and II alleles as predictors of sarcoidosis, the analysis was performed in two stages. {chi}2 test was used to assess the association of various alleles with sarcoidosis. While doing the multiple comparisons, P values were accordingly adjusted using Bonferroni correction for the number of comparisons made (P value was multiplied by 12 for DRB1, 8 for DQA1, and 13 for DQB1). Odds ratios (OR) and 95% confidence interval (CI) were used to quantify the association of various alleles with sarcoidosis. Alleles showing statistically significant association with sarcoidosis at P < 0.20 were considered as candidate predictors for inclusion in the multivariate model. Stepwise multivariate logistic regression was used with the potential predictor alleles as the co-variates. STATA 7.0 intercooled version (STATA corporation, Houston, TX) was used for data analysis. All statistical tests performed were two-tailed. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
HLA Class I Association
Among the class I antigens, HLA-B22 was significantly increased in patients with sarcoidosis as compared with healthy control subjects (19.4% versus 4.5%; P < 0.01). However, the difference was not statistically significant when the Bonferroni's correction was applied. None of the HLA-A and -Cw antigens tested differed significantly between the patients and control subjects. An analysis based on the reported nine different supertypes also showed a similar frequency distribution between the patients and control subjects (Table 1). The HLA-C specificities were analyzed based on their ligand properties to KIR receptors. Accordingly, the frequency of KIR2DL1 was found to be significantly increased in the patient group with sarcoidosis as compared with healthy control subjects (58.6% versus 29.8%; P < 0.01) (Figure 1).


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  		TABLE 1 HLA class I allele supertypes in patients with sarcoidosis and in healthy control subjects

 


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  		Figure 1. (A) Diagrammatic representation of Killer cell Ig-like receptors showing differences in the cytoplasmic domain (short and long tail, respectively, DS and DL variants) and its interaction with HLA-Cw alleles. (B) The percent frequency of Cw ligand groups with respect to the corresponding KIR2D receptors in patients with sarcoidosis and healthy control subjects. ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif.

 
HLA Class II Association
The phenotype frequencies of HLA-DRB1 and DQ alleles defined by low-resolution PCR-SSOP typing in patients with sarcoidosis and healthy control subjects are shown in Table 2. Among these DRB1*11 (35.7% versus 20.7%; P < 0.05), DRB1*14 (39.3% versus 17.8%; P < 0.001), DQA1*0101/4 (54.9% versus 34%; P < 0.01), DQB1*0402 (5.9% versus 0%; P < 0.01), and DQB1*0503 (39.2% versus 16%; P < 0.001) were significantly increased in the patients with sarcoidosis. On the other hand, the frequency of DQB1*0201(11.8% versus 36%; P < 0.001) was significantly reduced in the patient group. The frequency differences in DRB1*11, DQA1*0101/4, and DQB1*0402 was not statistically significant after the Bonferroni's correction applied. High-resolution typing of DR2, DR5, and DR6 alleles showed a strong positive association of DRB1*1404 (28.6% versus 10.6%; P < 0.001) in the diseased group as compared with healthy control subjects.


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  		TABLE 2 Distribution of HLA-DRB1 and DQ alleles in patients with sarcoidosis and in healthy control subjects

 
In the multivariate logistic regression analysis when all the candidate predictor alleles were simultaneously considered, presence of DRB1*11 (9-fold) and DRB1*14 (7-fold) was associated with increased risk of developing sarcoidosis. Similarly, absence of DRB1*07 (63-fold) and DQB1*0201 (3-fold) was associated with increased risk of developing sarcoidosis (Table 3).


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  		TABLE 3 HLA Class I and class II predictor alleles in sarcoidosis: results of bivariate and multivariate logistic regression analysis

 
Haplotype analysis of 48 patients and 118 healthy control subjects who had complete typing of DRB1, DQA1, and DQB1 alleles showed the presence of diverse number of haplotypes in the population. The frequently observed haplotypes in the two study groups are shown in Table 4. Of the haplotypes noticed among the sarcoidosis patients, presence of DRB1*11-DQA1*0501-DQB*0301 and DRB1*14-DQA1*0101/4-DQB1*05031 was associated with increased risk of disease development. Although haplotype DRB1*03-DQA1*0501-DQB1*0201 was negatively associated with the disease, the difference did not remain significant when Bonferroni's correction is applied.


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  		TABLE 4 HLA-DRB1 and DQ associated three locus haplotypes in sarcoidosis and healthy controls

 
Subgroup Analysis
To determine the role of specific HLA allelic association and disease prognosis, patients were subgrouped into different categories based on the disease onset, chronicity (disease activity beyond 2 yr), radiographic severity, and extrapulmonary manifestations such as joint, skin, and ocular involvement. Because the number of patients in each clinical subgroup is relatively small and multiple numbers of variables were studied in each group, the P values have been corrected by using Bonferroni's inequality test. Although no association was observed in patients with insidious disease onset, DRB1*14 and its linked DQ alleles (DQA1*0101/4 and DQB1*05031) showed strong positive association in patients with chronic disease course, stage II or III disease on chest radiographs, and also those with joint involvement (Figure 2).



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  		Figure 2. Selected DRB1 and DQ allele frequency in patients with various clinical categories of sarcoidosis such as insidious onset (n = 23) (lightly dotted bars), chronic disease course (n = 34) (hatched bars), stage II and III disease on chest radiograph (n = 37) (dotted bars), patients with joint involvement (n = 29) (checkered bars), and healthy control subjects (n = 275) (open bars). The statistical differences are represented in the form of corrected P value (*Pc < 0.01).

 
Treatment Follow Up and Pulmonary Function
Of the total patients with sarcoidosis, 53 were followed up for a period of 5 yr, and the laboratory tests and pulmonary functions were measured before and during the treatment period. The correlation of HLA class II alleles with the pulmonary function showed considerable difference among the disease-associated DR alleles, particularly with improvement in lung functions (vital capacity) among DRB1*11-positive and deterioration of lung function in DRB1*14-positive patients. However, these differences were not statistically significant. Further, analysis in patients who had frequent relapse of symptoms (40 of the 53 cases) on tapering off the dosages of prednisolone showed an overrepresentation of DRB1*14 (57% versus 18%; P < 0.05) and DQA1*0101/4 (71% versus 34%; P < 0.05) as compared with healthy control subjects.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This is the first comprehensive Indian study on the association of HLA alleles with sarcoidosis. Although no consistent HLA class II association has been reported with this disease in studies performed in various populations, the most consistent HLA class I allele found to be associated with sarcoidosis has been HLA-B8 (12, 16, 17, 28–30). Further, this allele is also associated with erythema nodosum and spontaneous resolution (17). Table 5 summarizes HLA data from various studies done worldwide. In the present study, class I alleles were investigated in 31 patients with sarcoidosis using the standard microlymphocytotoxicity assay, and none of them were found to have HLA-B8. This allele occurs with a frequency of 8.2% in the healthy North Indian population and often in linkage disequilibrium with A26 and not A1 (31). This highlights the race specificity of the association in different ethnic groups. It is also possible that genetic factors may be important in defining the pattern of disease presentation, progression, or overall prognosis. According to the recent description of HLA class I supertypes and the division of HLA-C locus alleles into two groups based on NK cell specificity, we re-evaluated the HLA class I data of the present study. These broad categories of HLA molecules, based on their function (common peptide-binding motif or NK cell receptor binding) provide new opportunities to investigate associations between HLA and infectious diseases. The observed overrepresentation of KIR ligands, particularly KIR2DL1, among patients is suggestive of predominant suppression of NK cell activity during the initial activation process by the sarcoid antigen.


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  		TABLE 5 Worldwide studies of HLA class I and II alleles in sarcoidosis

 
Not many studies in sarcoidosis have used molecular methods for investigating alleles at DRB1 (18, 19) and DQ loci (14, 19). In the present study, PCR–SSOP hybridization technique was employed to determine class II alleles, as these are not only more sensitive than serology, but can also define alleles at high-resolution level. The MHC class II region also plays a role in determining susceptibility to sarcoidosis in an apparently ethnic-dependent manner. The multivariate logistic regression analysis used in our study revealed that three HLA-DR and one HLA-DQ alleles may be associated with the development of sarcoidosis. Thus, absence of DRB1*07 (63-fold) and DQB1*0201 (3-fold), and presence of DRB1*11 (9-fold) and DRB1*14 (7-fold) alleles, were found to be independent predictors of disease development. However, the ethnic-independent association of these alleles has to be confirmed with large size in this population and also in other ethnic groups. Incidentally, DR11 (subtype of DR5) and DR14 (Subtype of DR6) have also been possibly associated with sarcoidosis in many other populations (Table 5). A comparison of the distribution of HLA alleles in patients with sarcoidosis and healthy control subjects involves multiple comparisons; nevertheless, conservative adjustment for these comparisons by the Bonferroni method reveals that the positive association of DRB1*14, DQA1*0101/4, and DQB1*0503, and the negative association of DQB1*0201 with sarcoidosis, remained statistically significant. The HLA-DQ molecules are unique among class II MHC molecules because both the {alpha} and ß chains are highly polymorphic, and most of the variable amino acid residues are located on the {alpha}-helical part of the antigen-binding site. Strikingly, the HLA–DRB1*01 and DRB1*04 alleles have been reported as "protective alleles" in six different ethnic cohorts of patients with sarcoidosis (18).

Consistent with the previous reports (19), we also observed an increased frequency of DRB1*14 in patients with chronic course, but did not confirm previous studies suggesting an association of DR3 with acute disease and good outcome progress in patients with sarcoidosis (12–15, 19, 32). In a recent European study involving patients from the United Kingdom, Poland, and the Czech Republic, HLA-DR*14 and -DR*15 occurred more frequently among patients than control subjects, whereas the frequency of DR3 was akin to that of the control subjects (18). Similarly, in the Scandinavian study, although HLA-DR3 was associated with the acute disease course, presence of DR*14 and DR*15 in a patient favored chronic disease (19). Likewise, DR3 was associated with acute disease in German patients (32) and with good disease outcome in the Italian and Czech study (15). Recently, Ishihara and coworkers (14) using molecular methods reported a significant increase of DRB1*11 in Japanese patients with sarcoidosis. These results suggests an ethnically dependent association of HLA-DR, -DQ alleles with sarcoidosis activation and disease outcome.

An increased frequency of DRB1*14, with insidious onset and advanced disease on chest radiographs, was also observed in the present study. However, no association was observed with ocular lesions in patients. This is in contrast to the report among Japanese patients (14), which recorded reduced frequencies of DR3, -5, -6, and -8 in those with ocular lesions.

In summary, the results of present study highlight the race specificity of the observed HLA association in various populations. Nonetheless, the observed association of HLA-DRB1*14 with the more advanced clinical disease in the present study points toward an important role of HLA-associated genes as possible predictors of disease outcome.


   Acknowledgments
 
The authors thank Ms. Yogita Dixit and Mr. Mukesh Singh for their help in the conduct of the study. This study was supported by the Department of Biotechnology, Division of Ministry of Science and Technology, Govt. of India (Grant No. BT/MB/05/005/HG/96 and BT/PRO585/MED/09/113/97).

Received in original form January 8, 2003

Received in final form February 11, 2003


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2003 American Thoracic Society.